1. Field of the Invention
The invention relates to and has among its objects the provision of novel stable plasma protein fractions and methods for making them. It is a particular object of the invention to obtain Plasma Protein Fractions (Human) substantially free of acetate ions and such fractions substantially free of blood pressure depressant components. Further objects of the invention will be evident from the following description wherein parts and percentages are by weight unless specified otherwise.
2. Description of the Prior Art
Solutions of heat-treated human Plasma Protein Fractions (PPF), e.g., those described in U.S. Pat. No. 2,958,628, have enjoyed widespread medical utilization for conditions requiring the use of a plasma expander, such as shock, hypoproteinemia, and the like. The need for stable human PPF has been recognized since the discovery that pooled normal human plasma had a rather high rate of infection with the virus of homologous serum jaundice.
For the most part, solutions of PPF are administered to the patient at a slow rate with minimal side-effects. Recently, however, marked depression of blood pressure and alteration of coronary flow (hereinafter referred to as vasodepressor activity) have been observed in patients infused with PPF solutions at relatively rapid rates. For many patients this vasodepressor activity is extremely dangerous.
The presence of a "depressor substance" in human PPF was recognized in U.S. Pat. No. 2,958,628 (hereinafter '628). The depressant activity was ascribed to Fraction IV-1, and Hink et al in Vox Sang., Vol. 2, pages 174-186 (1957) note that removal of Fraction IV-1 from solutions of PPF results in a material with reduced depressor activity.
Further reduction of depressor activity was obtained in U.S. Pat. No. 3,876,775 (hereinafter '775). The patentees described the blood pressure depressant substance as a polypeptide having a molecular weight between 1,000 and 10,000 and being generated primarily during the heating of PPF solutions for sterilization purposes. In the process of '775 solutions of heat-treated PPF were contacted with a surface active adsorbent, a cation exchanger, an ultrafiltration membrane, or gel filtration particles.
In U.S. Pat. No. 4,251,510 there is disclosed a plasma protein fraction substantially free of bradykinin, kininogen, and prekallikrein activators, which were recognized as imparting vasodepressor activity to the protein fraction. In the patented process Hink Supernatant II plus III is treated at neutrality with a siliceous substance for a period of time sufficient to bring about essentially complete conversion of intrinsic kininogen to bradykinin. Subsequently, after being separated from Hink Fraction IV-1, the plasma protein fraction is reconstituted, held for a period of time sufficient to allow substantially complete destruction of bradykinin by carboxypeptidase, and subjected to ultrafiltration and/or diafiltration to remove ethanol and residual bradykinin. Then, the retentate is constituted with sodium caprylate, N-acetyl-dl-tryptophan, sodium carbonate, sodium chloride, and sodium acetate.
Recently, in the Journal of Dialysis, Vol. 2, No. 3, pages 235-242 (1978) and in the Transactions of the American Society of Artificial Internal Organs, Vol. XXIII, pages 399-405 (1977), it was disclosed that acetate ions caused blood pressure depression when used as a fixed base in hemodialysis treatment of renal failure.
Sodium acetate is employed in the current commercial productions of PPF (human). Sodium acetate, together with stabilizing agents, is added to the solution of dried powder obtained from drying a wet paste precipitated from Effluent IV-1 to increase the sodium ion concentration of the solution of human PPF to within the range required for medical use, namely, 130-160 milliequivalents per liter (meq/l).